Ca²⁺/calmodulin-driven functions mediated by extracellular vesicles: a physiopathological perspective

Extracellular vesicles (EVs), including exosomes and microvesicles, secreted by a wide range of eukaryotic cells, are now well-established mediators of intercellular communication, acting through their uptake by recipient cells at local or distant sites. This occurs after delivering their cargo, a variety of RNAs, lipids, and proteins, which regulate many cellular functions in health and disease states. Among the exosomal cargos, the Ca²⁺-sensor protein calmodulin (CaM), as well as several Ca²⁺/CaM-regulated proteins, are frequently found in EVs, potentially playing important roles in the function of target cells. In addition, RNAs, which control the expression (mRNAs) or downregulation (miRNAs, lncRNAs) of Ca²⁺/CaM-regulated systems, are present in EVs, contributing to Ca²⁺ signaling processes when transferred into target cells. We discuss the involvement of exosomal CaM signaling systems in the pathophysiology of some high-incidence diseases affecting the heart and the nervous system. In this group, the contribution of Ca²⁺/CaM-regulated systems to tumor cells behavior in a wide range of organs is explored in more detail. In addition, some diseases of the kidneys, lungs, liver, the immune system, the eyes and the pancreas are considered. Finally, we highlight selected examples in which isolated exosomes modulating Ca²⁺/CaM pathways have been investigated as potential therapeutic agents.